Human steatohepatitis and the effects of HMGB1

Thesis

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease, affecting nearly 40% of the global population, and its prevalence continues to rise. MASLD ranges from simple steatosis to the more advanced stages of metabolic dysfunction-associated steatohepatitis (MASH) and cirrhosis. Individuals with cirrhosis are at risk of developing hepatocellular carcinoma and death. Although recent FDA approvals of resmetirom and semaglutide establish MASH as a druggable disease, their efficacy remains modest and comparable to lifestyle interventions, underscoring the need for improvement.

Therapeutic development has been hindered by an incomplete understanding of the mechanisms driving MASLD, compounded by the poor predictive value of animal models. I addressed these challenges by analysing patient-derived multi-omic data, which revealed mitochondrial bioenergetic deficits as a hallmark of advanced disease. I then developed 3 human in vitro models of MASH: fatty acid-challenged stem cell-derived hepatocyte-like cells, fatty acid-challenged primary hepatocytes isolated from healthy tissue and primary hepatocytes from steatotic livers with inherent mitochondrial dysfunction.

Using these systems, I investigated the effects of an engineered non-oxidisable construct (double Box B, dBB) of High Mobility Group Box 1, which was previously shown to promote repair of skeletal muscle. dBB improved hepatocellular mitochondrial function and viability following fatty acid challenge. Although current therapeutics have shown clinical benefit in human MASH, direct effects on mitochondria remain to be validated. Together, my findings highlight the potential for upregulating mitochondrial function in the more advanced stages of MASLD.

Authors: Guy, T

• DOI: 10.5287/ora-ozv6pyagy
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: Metabolic dysfunction-associated steatohepatitis (MASH); primary human hepatocyte-like cells; liver steatosis; metabolic dysfunction-associated steatotic liver disease (MASLD); stem cell-derived hepatocytes; in vitro
• Subjects: Mitochondria; Liver; Metabolic dysfunction-associated steatotic liver disease (MASLD)